The present invention relates to a new anthranilic acid derivative expressed by the formula (1) or the formula (2), its pharmacologically permissible salts or solvated products (which may be collectively called as xe2x80x9cthe anthranilic acid derivative of the present inventionxe2x80x9d hereinafter), a pharmaceutical composition composed thereof and a preventive and/or therapeutic agent composed thereof. More particularly, it relates to a new anthranilic acid derivative having benzene skeleton or pyridine skeleton on the principal anthranilic acid skeleton and further having a benzene skeleton or a naphthalene skeleton substituted by a side chain containing hetero-atom, i.e. a derivative having three aromatic groups at the same time, its pharmacologically permissible salt or solvated product, a pharmaceutical composition composed thereof and a preventive and/or therapeutic agent composed thereof.
Further, the anthranilic acid derivative of the present invention is a compound clinically applicable as a carcinostatic agent owing to its strong cytotoxic action and also clinically applicable as a preventive and/or therapeutic agent for allergic diseases owing to its activity to suppress the formation of IgE antibody.
Examples of the compound having naphthalene skeleton and anthranilic acid skeleton at the same time are those disclosed in the specification of JP-A 1-287066 (hereinunder, JP-A means xe2x80x9cJapanese Unexamined Patent Applicationxe2x80x9d). The specification describes compounds such as N-(2-naphthoyl)anthranylbenzoic acid and shows that these compounds have antiallergic activity or 5-lipoxygenase inhibiting activity. However, these compounds consist of a bicyclic aromatic ring derivative substituted by hydroxyl group or alkoxy group and directly bonded to an anthranilic acid skeleton through an amide bond, and there is no description or suggestion in the specification whether these compounds have cytotoxic action or IgE antibody production suppressing action or not.
Compounds having naphthalene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity are described in the specifications of JP-A 1-106818, International Application WO90/12001 and JP-A 7-285858. However, these compounds are different from the compound of the present invention because there is no compound having a principal skeleton containing three aromatic rings at the same time in these compounds.
International Application WO95/32943 and a document xe2x80x9cJournal of Medicinal Chemistry (J.Med.Chem.) vol.40, No.4, sections 395-407 (1997)xe2x80x9d describe compounds having naphthalene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity. Further, International Application WO97/19910 describes compounds having benzene skeleton and anthranilic acid skeleton and exhibiting antiallergic activity and IgE antibody production suppressing activity. However, these compounds are also different from the compound of the present invention because the substituent corresponding to the side chain of benzene skeleton or naphthalene skeleton is limited to alkoxy groups, alkenyloxy groups or aralkyloxy groups. Furthermore, the specification merely describes the presence of antiallergic activity and IgE antibody production suppressing activity in these compounds having the above specific substituents.
Compounds having pyridine ring skeleton and anthranilic acid skeleton and exhibiting antibacterial activity are described in the specification of International Application WO95/25723. The specification further describes that the substituent of the pyridine ring includes phenyloxy group and phenylthio group which may have substituents. However, there is no detailed explanation on the kind of the substituents. In the compounds of the present invention, for example, the pyridine ring is always substituted by phenyloxy group, phenylthio group, phenylsulfonyl group, phenylsulfinyl group, phenylcarbonyl group, phenylmethyl group, naphthyloxy group, naphthylthio group, naphthylsulfonyl group, naphthylsulfinyl group, naphthylcarbonyl group or naphthylmethyl group and furthermore the phenyl group or the naphthyl group constitutes the mother nucleus and always substituted by alkoxy group, aryloxy group, etc., which may contain hetero-atoms and, accordingly, the compound of the present invention is different from the compounds described in the above specification. Further, there is no comment on the IgE antibody production suppressing activity in the specification.
Meanwhile, the creation of a new compound having strong cytotoxic action is extremely important in the development of an excellent carcinostatic agent. Since the carcinostatic activity and carcinostatic spectrum of a compound are highly dependent upon its chemical structure in general, it is highly possible to enable the development of a carcinostatic agent having excellent characteristics compared with conventional carcinostatic agents practically in use at present from a cytotoxic compound having a new structure different from the structure of known compounds.
Examples of known low-molecular compound having benzene skeleton or aryl skeleton and exhibiting cytotoxic activity are substituted phenylsulfonyl derivative (JP-A 5-9170), 2-arylquinolinol derivative (JP-A 7-33743) and benzoylacetylene derivative (JP-A 7-97350).
However, the fact that a compound having benzene skeleton or aryl skeleton together with anthranilic acid skeleton has cytotoxic activity or carcinostatic activity is utterly unknown.
The object of the present invention is to provide a new compound usable as a clinically applicable therapeutic agent for cancer and preventive and/or therapeutic agent for allergic diseases.
As a result of vigorous investigation performed by the inventors of the present invention to achieve the above purpose, the inventors have found the following items 1 to 16 and completed the present invention.
In the description of atomic group expressing substituent, etc., the mark xe2x80x9cxe2x80x94xe2x80x9d showing the direction of bond is described in a group supposed to have ambiguous bonding form, however, the mark may be omitted for a group having clear bonding form.
1. The anthranilic acid derivative expressed by the following formula (1) or the following formula (2) or its pharmacologically permissible salt or solvate. 
 less than  less than in the formulas, Y1 is the group of the following formula (3)-1 or (3)-2. 
{in the formulas, Z is a straight-chain, branched or cyclic saturated, unsaturated or aromatic C1 to C12 hydrocarbon group substituted by one or more xe2x80x94NR10R11, xe2x80x94COOR12, xe2x80x94(Cxe2x95x90O)NR13R14, xe2x80x94(Cxe2x95x90O)R15 or OR16 [the C1 to C12 hydrocarbon group is optionally substituted by a substituent L (L is a C1 to C6 alkyl group, a halogen atom, xe2x80x94NO2 or xe2x80x94CN)],
a 3 to 8-membered saturated ring containing one or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups in the ring, a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring, or a C5 to C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring (the aromatic ring is optionally substituted by the substituent L).
the groups R10, R11, R12, R13, R14, R15, R16, and R17 are each independently hydrogen atom, a straight or branched-chain C1 to C6 alkyl group which is optionally substituted, a C7 to C11 aralkyl group which is optionally substituted, a C6 to C10 aryl group which is optionally substituted (the substituent is a halogen atom, xe2x80x94OH, a C1 to C4 alkoxy group, xe2x80x94CN, xe2x80x94NO2 or xe2x80x94COOR18), or a group selected from the following formulas (4)-1, (4)-2 and (4)-3. The groups R10 and R11, or R13 and R14 may together form a 3 to 12-membered ring optionally containing one or more xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR18xe2x80x94 or xe2x80x94(Cxe2x95x90O)xe2x80x94 groups. 
[in the formulas, Q is a C1 to C10 alkyl group which is optionally substituted, a C2 to C6 alkenyl group which is optionally substituted, a C1 to C6 alkoxy group which is optionally substituted, a C7 to C11 aralkyl group which is optionally substituted, a C7 to C11 aralkyloxy group which is optionally substituted (the substituent is a halogen atom, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COOR19 or phenoxy group), dimethylamino group, morpholino group or a monocyclic or bicyclic aromatic hydrocarbon group which may have one or more hetero-atoms selected from oxygen, nitrogen and sulfur atoms. [when a monocyclic or bicyclic aromatic hydrocarbon group which may have one or more hetero-atoms is selected in the above case, the ring is optionally substituted at arbitrary positions independently by one or plural substituents selected from halogen atom, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOR19, NR19R20, straight or branched-chain C1 to C6 alkyl group, straight or branched-chain C1 to C6 alkoxy group (in this case, the substituents at adjacent positions may form an acetal bond), straight or branched-chain C1 to C6 alkylthio group, straight or branched-chain C1 to C6 alkylsulfonyl group, straight or branched-chain C1 to C6 acyl group, straight or branched-chain C1 to C6 acylamino group, trihalomethyl group, trihalomethoxy group, phenyl group, or phenoxy group which is optionally substituted by one or more halogen atoms],
the groups R19 and R20 are each independently hydrogen atom or a C1 to C4 alkyl group],
the group R18 is hydrogen atom or a C1 to C4 alkyl group,
the group X3 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, SO2, xe2x80x94NR21xe2x80x94, *xe2x80x94NR21(Cxe2x95x90O) or *xe2x80x94(Cxe2x95x90O)NR21 (the sign (*xe2x80x94) representing a bond means the bonding to the benzene ring or the naphthalene ring in the formula (3)-1 or the formula (3)-2),
the group R21 is hydrogen atom or a C1 to C4 hydrocarbon group which is optionally substituted by a halogen,
the groups R5 and R6 are each independently hydrogen atom, a halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR22, xe2x80x94NH(Cxe2x95x90O)R22, xe2x80x94(Cxe2x95x90O)NHR22 or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group which is optionally substituted by halogen atom,
the group R22 is a C1 to C3 hydrocarbon group which is optionally substituted by hydrogen atom or halogen atom},
the group Y2 is the formula (3)-1, the formula (3)-2, the following formula (5)-1 or the following formula (5)-2, 
 less than in the formulas, the group R7 is hydrogen atom or a substituted or unsubstituted straight-chain, branched or alicyclic saturated or unsaturated C1 to C12 hydrocarbon group having one or two double bonds or triple bonds [in this case, the substituent is a halogen atom, xe2x80x94NO2, xe2x80x94CN, a substituted or unsubstituted phenyl group (in this case, the substituent is a halogen atom, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3 or a C1 to C4 hydrocarbon group), or a substituted or unsubstituted 5 to 8-membered cycloalkyl group (in this case, the substituent is a halogen atom or a C1 to C4 hydrocarbon group)],
the group X4 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, xe2x80x94NR23xe2x80x94, *xe2x80x94NR23CO or *xe2x80x94CONR23 (the group R23 is hydrogen atom or a C1 to C4 hydrocarbon group, which is optionally substituted by halogen atom. In this case, the sign (*xe2x80x94) means the bonding to the benzene ring or the naphthalene ring of the formula (5)-1 or the formula (5)-2. The group R7 is not hydrogen atom when the group X4 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94 or *xe2x80x94NR23(Cxe2x95x90O)xe2x80x94,
the groups R8 and R9 are each independently hydrogen atom, a halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR24, xe2x80x94NH(Cxe2x95x90O)R24, xe2x80x94(Cxe2x95x90O)NHR24 or a straight or branched-chain saturated or unsaturated C1 to C4 hydrocarbon group which is optionally substituted by halogen atom (the group R24 is hydrogen atom or a C1 to C3 hydrocarbon group which is optionally substituted by halogen atom) greater than ,
the group X1 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94 or xe2x80x94CH2xe2x80x94,
the group X2is O or S,
the groups R1 and R2 are each independently hydrogen atom, a halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR25, xe2x80x94NH(Cxe2x95x90O)R25, xe2x80x94(Cxe2x95x90O)NHR25 or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group which is optionally substituted by halogen atom,
the group R25 is hydrogen atom or a C1 to C3 hydrocarbon group which is optionally substituted by halogen atom,
the groups R3 and R4 are each independently hydrogen atom or a C1 to C4 hydrocarbon group,
the group A is N, Nxe2x86x92O or N+xe2x80x94CH3, and
n is an integer of 0 to 3. greater than  greater than .
2. The above anthranilic acid derivative wherein Y2 is the group of the formula (3)-1 or the formula (3)-2 or its pharmacologically permissible salt or solvate.
3. An anthranilic acid derivative expressed solely by the formula (1), or its pharmacologically permissible salt or solvate.
4. An anthranilic acid derivative expressed solely by the formula (2) wherein the group Y2 is expressed by the formula (3)-1 or the formula (3)-2, or its pharmacologically permissible salt or solvate.
5. An anthranilic acid derivative expressed solely by the formula (2) wherein the group Y2 is expressed by the formula (5)-1 or the formula (5)-2, or its pharmacologically permissible salt or solvate.
6. An anthranilic acid derivative of the formula (1) wherein the group Y1 is expressed by the following formula (9)-1, (9)-2 or (9)-3, or its pharmacologically permissible salt or solvate. 
 less than in the formula, the definitions of Z, X3, R5 and R6 are same as those of the formula (3)1 or the formula (3)-2 greater than 
7. An anthranilic acid derivative of the formula (2) wherein the group Y2 is expressed by the formula (5)-1, the formula (5)-2, the formula (9)-1, the formula (9)-2 or the formula (9)-3, or its pharmacologically permissible salt or solvate.
8. The anthranilic acid derivative of the formula (1) or the formula (2) wherein the group Z is a straight-chain, branched or cyclic saturated, unsaturated or aromatic C1 to C12 hydrocarbon group substituted by one or more xe2x80x94NR10R11, xe2x80x94COOR12, xe2x80x94(Cxe2x95x90O)NR13R14, xe2x80x94(Cxe2x95x90O)R15 or xe2x80x94OR16 [the C1 to C12 hydrocarbon group is optionally further substituted by substituent L (L is a C1 to C6 alkyl group, halogen atom, xe2x80x94NO2 or xe2x80x94CN)], or its pharmacologically permissible salt or solvate.
9. An anthranilic acid derivative of the formula (1) or the formula (2) wherein the group Z is a saturated 3 to 8-membered ring containing one or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 groups and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups in the ring, or a C1 to C4 straight or branched-chain saturated or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring, or its pharmacologically permissible salt or solvate.
10. The anthranilic acid derivative of the formula (1) or the formula (2) wherein the group Z is a C5 to C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring (the aromatic ring is optionally substituted by a substituent L), or its pharmacologically permissible salt or solvate.
11. A pharmaceutical composition composed of the above anthranilic acid derivative or its pharmacologically permissible salt or solvate, and a pharmacologically permissible carrier.
12. The above pharmaceutical composition having cytotoxic activity.
13. A therapeutic agent for cancer composed of the above pharmaceutical composition.
14. The above pharmaceutical composition having IgE antibody production suppressing action.
15. A preventive or therapeutic agent for allergic diseases composed of the above pharmaceutical composition.
16. The above preventive or therapeutic agent wherein said allergic diseases are bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis or drug-induced rash.
The present invention is described in more detail as follows.
In the formula (1) expressing the anthranilic acid derivative of the present invention, Y1 is a group selected from the formula (3)-1 and the formula (3)-2. 
In the formulas, ZX3, R5 and R6 are substituted one for each to the benzene ring or the naphthalene ring, however, the group ZX3xe2x80x94 is preferably positioned at a site expressed in the following formulas (9)-1 to (9)-3. 
R5 and R6 are each independently hydrogen atom, a halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR22, xe2x80x94NH(Cxe2x95x90O)R22 or xe2x80x94(Cxe2x95x90O)NHR22 or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom, and preferably hydrogen atom, a halogen atom, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94NH(Cxe2x95x90O)CH3, xe2x80x94(Cxe2x95x90O)NHCH3 or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom. More preferably, it is hydrogen atom, a halogen atom, xe2x80x94CH3, xe2x80x94OH or xe2x80x94OCH3 and, especially, hydrogen atom.
In the formula (3)-1 or the formula (3)-2, Z is a C1xe2x80x94C12 (the carbon number is restricted to those allowable from its structure) straight, branched or cyclic saturated or unsaturated hydrocarbon group or aromatic hydrocarbon group substituted by one or more substituents selected from xe2x80x94NR10OR11, xe2x80x94COOR12, xe2x80x94(Cxe2x95x90O)NR13R14, xe2x80x94(Cxe2x95x90O)R15 and xe2x80x94OR16 and optionally substituted by a substituent L, or a saturated 3 to 8-membered ring having one or plural NR17, O or S in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups in the ring or a C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by a C1-C4 straight or branched-chain or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by the above 3 to 8-membered ring or by a monocyclic or bicyclic aromatic ring (which may be substituted by the substituent L) containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur. The carbon number of the C1-C12 hydrocarbon group of Z is the number of carbon atoms of the main chain and the carbon numbers of the substituents are not included in the carbon number.
When the group Z is a C1-C12 straight, branched or cyclic saturated or unsaturated hydrocarbon or an aromatic hydrocarbon, it is for example methyl group, ethyl group, propyl group, butyl group, isobutyl group, hexyl group, 2-ethylpropyl group, 1,1-dimethylethyl group, allyl group, methallyl group, cyclohexyl group, cyclooctyl group, cyclopentylmethyl group, cyclohexenylmethyl group, 1-decalyl group, phenyl group, benzyl group and phenylpropyl group, and especially preferably methyl group, ethyl group, cyclohexyl group, cyclopentylmethyl group, benzyl group or phenylpropyl group. These hydrocarbon groups are substituted by one or more xe2x80x94NR10R11, xe2x80x94COOR12, xe2x80x94(Cxe2x95x90O)NR13R14, xe2x80x94(Cxe2x95x90O)R15 or xe2x80x94OR16 groups.
In the definitions of the formula (3)-1 and the formula (3)-2, the group Z is a saturated 3 to 8-membered ring containing one, or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 groups in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups, or a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds wherein these hydrocarbon groups may be substituted by the above 3 to 8-membered ring.
When Z is a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds wherein these hydrocarbon groups may be substituted by a saturated 3 to 8-membered ring containing one or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 groups in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups, the number of carbon atoms of the C1-C4 hydrocarbon does not include the carbon number of the ring. The substitution position of the main chain on the ring is an arbitrary carbon atom constituting the ring. In the above sentence, the main chain means a C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds.
When the group Z is a saturated 3 to 8-membered ring containing one or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 groups in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups, the substitution position of the group X3 defined in the formula (3)-1 and the formula (3)-2 is an arbitrary carbon atom constituting the ring.
The saturated 3 to 8-membered ring containing one or plural xe2x80x94NR17xe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 groups in the ring and optionally containing one or more xe2x80x94C(xe2x95x90O)xe2x80x94 groups is, for example, pyrrolidine ring, piperidine ring, pyrrolidone ring, piperazine ring, morpholine ring, thiomorpholine ring, tetrahydropyran ring and tetrahydrothiophene ring and especially preferably pyrrolidine ring, piperidine ring and piperazine ring.
In the C1-C4 straight or branched-chain saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds and substituted by a 3 to 8-membered ring, the straight-chain group is e.g. methyl group, ethyl group, n-propyl group, n-butyl group, 2-propenyl group, 3-butenyl group and 2-propynyl group, preferably methyl group, ethyl group, n-propyl group or n-butyl group, especially preferably methyl group or ethyl group.
The branched-chain group is e.g. isopropyl group, t-butyl group and 2-methylpropyl group and, among the above examples, isopropyl group and t-butyl group are preferable. In the definition in the formula (3)-1 and the formula (3)-2, the group Z is a C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by monocyclic or bicyclic aromatic ring (the aromatic ring may be substituted by a substituent L) containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring.
The term xe2x80x9cC5-C10xe2x80x9d means the total number of carbon atoms including the carbon atoms of substituents.
The monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring is, for example, pyridine ring, furan ring, thiophene ring, quinoline ring, pyrazole ring, imidazole ring, thiazole ring, triazole ring, benzofuran ring, thianaphthalene ring, indole ring and benzimidazole ring. Among the above examples, pyridine ring, furan ring, thiophene ring and quinoline ring are preferable and pyridine ring is especially preferable.
Examples of the C5-C10 straight or branched-chain saturated or unsaturated hydrocarbon group substituted by these aromatic rings are 4-pyridylmethyl group, 3-furanylmethyl group, 3-thiophenylethyl group, 2-quinolin-4-ylmethyl group and 3-pyridylethyl group and especially preferably 4-pyridylmethyl group.
The monocyclic or bicyclic aromatic ring containing one or more hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring may be substituted by a substituent L, and such substituent L is selected from C1-C6 alkyl group, halogen atom, xe2x80x94NO2 and xe2x80x94CN, for example, methyl group, ethyl group, isobutyl group, 1-ethylpropyl group, chloro group, bromo group, nitro group and nitrile group and, among the above examples, methyl group, ethyl group and chloro group are preferable.
The groups R10, R11, R12, R13, R14, R15, R16 and R17 are each independently hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituent, a C7-C11 aralkyl group which may have substituent, a C6-C10 aryl group which may have substituent (these substituents are halogen atom, OH, C1-C4 alkoxy group, xe2x80x94CN, xe2x80x94NO2 or xe2x80x94COOR18), or a group selected from the formula (4)-1, the formula (4)-2 and the formula (4)-3 or R10 and R11, or R13 and R14 together form a 3 to 12-membered ring which may contain one or more xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR18xe2x80x94 or xe2x80x94(Cxe2x95x90O)xe2x80x94 groups in the ring. Preferable examples of the groups R10, R11, R12, R13, R14, R15, R16 and R17 are hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C6-C10 aryl group which may have substituents (these substituents are C1-C4 alkoxy group or COOR18) or a group selected from the formula (4)-1, the formula (4)-2 and the formula (4)-3. 
When these groups are hydrogen atom, a C1-C6 straight or branched-chain alkyl group which may have substituents, a C7-C11 aralkyl group which may have substituents or a C6-C10 aryl group which may have substituents, examples of the groups are hydrogen atom, methyl group, ethyl group, isopropyl group, n-butyl group, pentyl group, hexyl group, benzyl group, phenyl group and naphthyl group, preferably methyl group, ethyl group, benzyl group and phenyl group. These group may be substituted by halogen atom, xe2x80x94OH, a C1-C4 alkyl group, xe2x80x94CN, xe2x80x94NO2 or xe2x80x94COOR18, and the substituent is preferably xe2x80x94Cl, xe2x80x94OH, ethoxy group, xe2x80x94CN or xe2x80x94COOH.
When the groups R10 and R11 or R13 and R14 together form a 3 to 12-membered ring, the ring may contain O, S or NR18. Concretely, the ring is e.g. pyrrolidine ring, piperidine ring, pyrrolidone ring, piperazine ring, morpholine ring, thiomorpholine ring, etc., and above all, pyrrolidine ring, piperidine ring, piperazine ring and morpholine ring are preferable. When the ring is e.g. piperazine ring, the nitrogen atom of the ring may be substituted by a C1-C4 lower alkyl group, i.e. R18, and in this case, the substituent is especially preferably methyl group or isopropyl group.
In the formula (3)-1 or the formula (3)-2, the group X3 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, xe2x80x94NR21, *xe2x80x94NR21(Cxe2x95x90O)xe2x80x94 or *xe2x80x94(Cxe2x95x90O)NR21 (the sign (*xe2x80x94) representing a bond means the bonding to the benzene ring or the naphthalene ring). The group is e.g. xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(CH3)(Cxe2x95x90O)xe2x80x94 or xe2x80x94(Cxe2x95x90O)NCH3 and especially preferably xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
In the formula (4)-1, the formula (4)-2 and the formula (4)-3, the group Q is a C2-C10 alkyl group which may have substituents, a non-substituted C1-C6 alkenyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C7-C11 aralkyloxy group which may have substituents, dimethylamino group, morpholino group or a monocyclic or bicyclic aromatic hydrocarbon group which may contain one or plural hetero-atoms selected from oxygen, nitrogen and sulfur atom in the ring.
When the group Q is a C1-C10 alkyl group which may have substituents, a C1-C6 alkenyl group which may have substituents, a C1-C6 alkoxy group which may have substituents, a C7-C11 aralkyl group which may have substituents, a C7-C11 aralkyloxy group which may have substituents, the concrete examples of the group are methyl group, ethyl group, propyl group, heptyl group, methoxy group, allyl group, benzyl group, phenylpropyl group and benzyloxy group. These groups may be substituted by halogen atom, xe2x80x94OH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94COOR19 or phenoxy group. Concretely, preferable substituent is chloro group, xe2x80x94OH, xe2x80x94COOH or phenoxy group.
When the group Q is a monocyclic or bicyclic aromatic hydrocarbon group which may contain one or plural hetero-atoms selected from oxygen, nitrogen and sulfur atoms in the ring, any one of the groups described in the following formula (10) can be selected as the aromatic hydrocarbon group. 
These groups are bonded to the amide group, carboxyl group or sulfonyl group in the formula (4)-1, the formula (4)-2 or the formula (4)-3 as the group Q at an arbitrary possible position, and may be bonded with the following groups at the remaining positions. Namely, the groups may be substituted by one or plural groups independently selected from halogen atom, xe2x80x94OH, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOR19, xe2x80x94NR19R20, a straight or branched-chain C1-C6 alkyl group, a straight or branched-chain C1-C6 alkoxy group (in this case, an acetal bond may be formed at the sites adjacent to each other as the substituents), a straight or branched-chain C1-C6 alkylthio group, a straight or branched-chain C1-C6 alkylsulfonyl group, a straight or branched-chain C1-C6 acyl group, a straight or branched-chain C1-C6 acylamino group, trihalomethyl group, trihalomethoxy group, phenyl group, or phenoxy group which may be substituted by one or more halogen atoms. In the above description, R19 and R20 are each hydrogen atom or a C1-C4 lower alkyl group.
Concrete examples of preferable substituents are xe2x80x94COOH, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94NH(Cxe2x95x90O)CH3, xe2x80x94(Cxe2x95x90O)CH3, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94CN, xe2x80x94OCH3, xe2x80x94Ph, xe2x80x94CH3, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, xe2x80x94CH3, xe2x80x94SCH3 and xe2x80x94OPh.
In the above formula (2), Y2 is the group of formula (3)-1, the formula (3)-2, the formula (5)-1 or the formula (5)-2. Among the groups expressed by the formula (3)-1 or the formula (3)-2, the preferable groups are, as mentioned before, the groups of the formula (9)-1, (9)-2 or (9)-3. 
In the formula (5)-1 or the formula (5)-2, the group R7 is hydrogen atom or optionally substituted straight, branched or alicyclic C1-C12 saturated hydrocarbon group or unsaturated hydrocarbon group containing one or two double bonds or triple bonds [in this case, the substituent is halogen atom, xe2x80x94NO2, xe2x80x94CN, an optionally substituted phenyl group (the substituent is halogen atom, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3 or a C1-C4 hydrocarbon group) or an optionally substituted 5 to 8-membered cycloalkyl group (the substituent is halogen atom or a C1-C4 hydrocarbon group)].
Each of the above groups has a total carbon number of 1 to 12 including the substituents. The cyclic saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds does not include aromatic rings such as benzene ring and hetero-aromatic ring, and the ring is directly bonded to the group X4 in the formula (5)-1 or the formula (5)-2. That is to say, the cyclic means alicyclic. In other words, these rings are free from oxygen, sulfur, nitrogen atom and carbonyl group in the ring, and the preferable examples of the ring are cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cyclooctane ring cycloheptane ring, cyclododecane ring, norbornene ring and cyclohexene ring. Cyclopentane ring, cyclohexane ring, cyclooctane ring and cyclododecane ring are more preferable among the above examples.
The straight-chain saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds is, for example, methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, n-octyl group, n-dodecyl group, 2-propenyl group, 3-butenyl group, 4-hexenyl group, 3-hexenyl group, 3-nonenyl group, 2,4-hexadienyl group and 2-propynyl group, preferably methyl group, ethyl group, n-propyl group, n-butyl group, n-hexyl group, 2-propenyl group, 3-butenyl group, 4-hexenyl group, 3-hexenyl group, 2,4-hexadienyl group or 2-propynyl group.
The branched saturated or unsaturated hydrocarbon group is, for example, isopropyl group, t-butyl group, ethylpropyl group, ethylpentyl group, 4-methylpentyl group, 2-ethylbutyl group, 2-methylpropyl group, 2-methylbutyl group, 2,4,4-trimethylpentyl group, 2-methylheptyl group, 3-methyl-1-(2-methylpropyl)butyl group, 2-methyl-1-(methylethyl)propyl group, 3-methyl-3-butenyl group, 3-methyl-2-butenyl group, 1-vinyl-2-propenyl group, 4-methyl-3-pentenyl group, 1-allyl-3-butenyl group, 1-ethyl-2-propenyl group, 1-propyl-2-propenyl group and 1-ethyl-2-propynyl group. Symmetric groups are preferable among the above groups. Especially preferable groups are ethylpropyl group and 2-ethylbutyl group.
The substituent of R7 is halogen atom, xe2x80x94NO2, xe2x80x94CN, a substituted or non-substituted phenyl group (the substituent is selected from halogen atom, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CF3 and C1-C4 hydrocarbon group) and a substituted or non-substituted 5 to 8-membered cycloalkyl group (the substituent is selected from halogen atom and a C1-C4 hydrocarbon group).
In the substituent of R7, the substituted or non-subsititted phenyl group (the substituent is selected from halogen atom, xe2x80x94NO2xe2x80x94, xe2x80x94CN, xe2x80x94CF3 and a C1-C4 hydrocarbon group) is, for example, phenyl group, m-fluorophenyl group, p-chlorophenyl group, m-iodophenyl group, p-fluorophenyl group, 2,4-dichlorophenyl, 3,5-difluorophenyl group, p-nitrophenyl group, m-nitrophenyl group, p-methylthiophenyl group, o-cyanophenyl group, p-cyanophenyl group, m-trifluoromethylphenyl group, p-methylphenyl group, p-isopropylphenyl group, p-t-butylphenyl group and 3,4-dimethylphenyl group.
The 5 to 8-membered cycloalkyl group as the substituent of the group R7 may be substituted by halogen atom or C1-C4 hydrocarbon group. Preferable examples of the C1-C4 hydrocarbon group are methyl group and ethyl group. Namely, examples of the optionally substituted 5 to 8-membered cycloalkyl group are cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, 2-chlorocyclohexyl group, 2-methylcyclohexyl group, 2-ethylcyclohexyl group, 3-methylcyclohexyl group, 4-methylcyclohexyl group, 4-(i-propyl)cyclohexyl group, 2,6-dimethylcyclohexyl group and 3,5-dimethylcyclohexyl group.
The group R7 is preferably hydrogen atom, a straight or branched-chain C1-C12 saturated hydrocarbon group or unsaturated hydrocarbon group having one or two double bonds or triple bonds and optionally substituted by halogen atom, or a group expressed by the following formulas. 
[in the formula, n1 is an integer of 1 to 3, n3 is an integer of 0 to 3, n2 is an integer of 0 to 9 (when n3 is 0) or an integer of 2 to 5 (when n3 is an integer of 1 to 3), R26 and R27 are each independently hydrogen atom, halogen atom, NO2, CN, CF3 or a C1-C4 hydrocarbon group, and R28 is hydrogen atom or a C1-C4 hydrocarbon group]. (The groups R26 and R27 are more preferably hydrogen atom, halogen atom or NO2).
The group R7 is especially preferably hydrogen atom or a group selected from the groups expressed by the following formula (12). 
The group X4 in the formula (5)-1 or the formula (5)-2 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, xe2x80x94NR23xe2x80x94, *xe2x80x94NR23(Cxe2x95x90O)xe2x80x94 or *xe2x80x94(Cxe2x95x90O)NR23. (The sign (xe2x80x94) representing a bond is bonded to the benzene ring or the naphthalene ring having R8 and R9, R23 is hydrogen atom or a C1-C4 hydrocarbon group which may be substituted by halogen atom. R7 is not hydrogen atom when X4 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94 or *xe2x80x94NR23(Cxe2x95x90O)xe2x80x94.). X4 is preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94 or xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, more preferably xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and especially preferably xe2x80x94Oxe2x80x94.
R23 is preferably hydrogen atom, methyl group or ethyl group, especially preferably hydrogen atom.
In the formula (5)-1 and the formula (5)-2, the groups R8 and R9 are each independently hydrogen atom, halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR24, xe2x80x94NH(Cxe2x95x90O)R24, xe2x80x94(Cxe2x95x90O)NHR24 or a straight or branched-chain saturated or unsaturated C1-C4 hydrocarbon group which may be substituted by halogen atom (the group R24 is hydrogen atom or a C1-C3 hydrocarbon group which may be substituted by halogen atom.). It is preferably hydrogen atom, halogen atom, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94NH(Cxe2x95x90O)CH3, xe2x80x94(Cxe2x95x90O)NHCH3 or a straight or branched-chain saturated or unsaturated C1-C4 hydrocarbon group which may be substituted by halogen atom. It is more preferably hydrogen atom, halogen atom, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94OH, ethyl group, isopropyl group, t-butyl group, allyl group or trifluoromethyl group, further preferably hydrogen atom, halogen atom, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94OH or trifluoromethyl group and especially preferably hydrogen atom.
When the group R24 is a C1-C3 hydrocarbon group which may be substituted by halogen, it is, for example, methyl group, ethyl group, isopropyl group and trifluoromethyl group and preferably methyl group or trifluoromethyl group.
In the formula (1) or the formula (2), X1 is xe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94, xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94 or xe2x80x94CH2xe2x80x94, preferably xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94(Sxe2x95x90O)xe2x80x94 or xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94, especially preferably xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
In the formula (1) or the formula (2), X2 is O or S, preferably O.
In the formula (1) or the formula (2), R1 and R2 are each independently hydrogen atom, halogen atom, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, xe2x80x94OR25, xe2x80x94NH(Cxe2x95x90O)R25, xe2x80x94(Cxe2x95x90O)NHR25 or a C1-C4 straight or branched-chain saturated or unsaturated hydrocarbon group which may be substituted by halogen atom. Concrete examples of the groups are hydrogen atom, chloro group, bromo group, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, methoxy group, ethoxy group, chloromethoxy group, butoxy group, acetylamide group, propionylamide group, methylaminocarbonyl group, butylaminocarbonyl group, methyl group, bromoethyl group, allyl group and chloropropenyl group, and preferably hydrogen atom, halogen atom (especially chloro group), xe2x80x94OH, xe2x80x94NO2, xe2x80x94CO2H, xe2x80x94CN, methoxy group, chloromethoxy group, acetylamide group, methylaminocarbonyl group or methyl group.
In the formula (1) or the formula (2), R3 and R4 are each independently hydrogen atom or a C1-C4 hydrocarbon group. Concrete examples of the groups are hydrogen atom, methyl group, ethyl group, propyl group and butyl group and preferably hydrogen atom or methyl group.
In the formula (1) or the formula (2), n is an integer of 0 to 3, preferably 0 or 1.
In the formula (2), A is N, Nxe2x86x92O or N+xe2x80x94CH3, preferably N or N or Nxe2x86x92O, more preferably N.
The anthranilic acid derivative of the present invention or its pharmacologically permissible salt can be converted into solvate at need. The solvent usable in the conversion process is water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMSO, DMF, etc., preferably water, methanol, ethanol, (n- or i-)propyl alcohol or acetonitrile.
When the compound of the formula (1) or the formula (2) has CO2H group in the molecule, the anthranilic acid derivative of the present invention can be converted as necessary into a non-toxic cation salt or its solvate. Examples of such salt are alkali metal ion such as Na+ and K+, alkaline earth metal ion such as Mg2+ and Ca2+, metal ion such as Al3+ and Zn2+, or organic base such as ammonia, triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, and N-methylglucamine, preferably Na+, Ca2+, lysine, choline, N,N-dimethylethanolamine and N-methylglucamine. The solvents for forming the solvates of these salts are, for example, water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF and DMSO, especially preferably water, methanol, ethanol, (n- or i-)propyl alcohol and acetonitrile.
When the compound of the formula (1) or the formula (2) contains primary, secondary or tertiary amine group in the molecule, the anthranilic acid derivative of the present invention can be converted as necessary into an acid addition salt or its solvate. The acid for the production of the acid addition salt is a mineral acid such as hydrochloric acid, sulfuric acid and nitric acid or an organic acid such as acetic acid, benzoic acid, fumaric acid, maleic acid, methanesulfonic acid and toluenesulfonic acid. Preferable acids among the above examples are hydrochloric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid and toluenesulfonic acid. The solvent for the production of the solvate of the salt is, for example, water, methanol, ethanol, (n- or i-)propyl alcohol, (n- or t-)butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF and DMSO, and preferably water, methanol, ethanol, (n- or i-)propyl alcohol and acetonitrile.
Concrete preferable examples of the compounds expressed by the formula (1) or the formula (2) of the present invention are compounds described in the Table 1 to the Table 43, their pharmacologically permissible salts or their solvates.
The anthranilic acid derivative of the present invention has strong cytotoxic activity and/or IgE antibody production suppressing activity. Concretely, as for cytotoxic activity, LC50 or GI50 is 5,000 nM or less, preferably 0.05 nM to 1,000 nM, more preferably 0.05 nM to 500 nM. As for IgE antibody production suppressing activity, IC50 is 1,000 nM or less, preferably 0.05 nM to 500 nM, more preferably 0.05 M to 100 nM.
The anthranilic acid derivative of the present invention having such an excellent cytotoxic activity can be used as a therapeutic agent clinically applicable to cancer. Since the anthranilic acid derivative of the present invention further has excellent IgE antibody production suppressing activity, compounds having relatively weak cytotoxicity among the above compounds are rather suitable for the use as a preventing agent and/or therapeutic agent clinically applicable to various allergic diseases.
The derivative of the present invention expressed by the aforementioned formula (1) or formula (2) or its pharmacologically permissible salt can be produced for example according to the following scheme. 
Namely, an aryl derivative [I] or [VI] having a group expressed by Z1X3 or Z1X4 (Z1 is hydrogen atom, a general protecting group such as benzyl group, benzoyl group, methoxymethyl group, acetyl group or trimethylsilyl group, the group Z defined in the formula (3)-1 and the formula (3)-2 or the group R7 defined in the formula (5)-1 or the formula (5)-2) and a carboxylic acid group is coupled with an anthranilic acid derivative [II] under a proper condition to enable the production of the compounds [III] and [VII] from the starting compounds [I] and [VI], respectively. The group Z1 of the produced compound [III] or [VII] is deprotected to obtain respective intermediate [IV] or [VIII] and a side chain Z is introduced into the compound [IV] to obtain the compound [V] or a side chain Z or a group R7 is introduced into the compound [VIII] to obtain a compound [IX]. When the group xe2x80x94CO2R3 is an ester, the product can be converted as necessary into a carboxylic acid by hydrolyzing the ester of the compound [V] or [IX]. When the group Z1 in the compound [III] or [VII] is Z or R7 defined before, the compound [III] or [VII] becomes the objective compound [V] or [IX], respectively, and when the group xe2x80x94CO2R3 is an ester, the ester [III] and [VII] can be converted as necessary into a carboxylic acid by hydrolysis.
The definitions of the groups A, Z, X1 to X4, R1 to R9 and n in the above formulas are same as the definitions in the formulas (1), (2), (3)-1, (3)-2, (5)-1 and (5)-2. There is no restriction on the production process of the starting substances [I] and [VI], and these compounds can be produced by known conventional methods.
The compounds [V] and [IX] are concretely synthesizable as follows.
The condensation of the compound [I] or [VI] to the compound [II] can be roughly classified into a method through an acid halide and an activation method without passing through an acid halide and either method is principally a known method.
In the case of passing through an acid halide, the objective compounds [III] and [VII] can be produced from the compounds [I] and [II] and the compounds [VI] and [II], respectively, by treating the compound [I] or [VI] with a proper halogenation agent such as oxalyl chloride and thionyl chloride in the presence or absence of an additive such as DMF in a proper solvent (e.g. methylene chloride or tetrahydrofuran) and reacting the produced acid halide with the compound [II] in the presence or absence of a proper base (e.g. triethylamine or potassium carbonate).
In the activation method which does not go through an acid halide, the objective compounds [III] and [VII] can be produced from the compounds [I] and [II] and the compounds [VI] and [II], respectively, by activating the compound [I] or [VI] with a proper activation agent such as mixed acid anhydride, carbodiimides, imidazolation agent, halophosphoric acid esters or cyanophosphoric acid esters in a proper solvent (e.g. methylene chloride or tetrahydrofuran) and reacting the activated compound with the compound [II].
The group Z1 in Z1X3 of the compounds [III] and [VII] may be Z and in Z2X4 may be R1 itself. When X3 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR21 or xe2x80x94(Cxe2x95x90O)NR21 (in this case, the carbonyl group is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2, and the definition of R21 is same as the definition in the formula (3)-1 and the formula (3)-2) or X4 iS xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR23xe2x80x94 or xe2x80x94(Cxe2x95x90O)NR23 (in this case, the carbonyl group is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2 and the definition of R23 is same as the definition in the formula (5)-1 and the formula (5)-2), the compound [IV] or [VIII] can be used as an intermediate after deprotection by using a proper protecting group (for example, ethers of benzyl group, allyl group, etc., silyl ethers of t-butyldimethylsilyl group, etc., esters of benzoyl group, etc., carbonates such as allyl carbonate, etc. when X3 or X4 is xe2x80x94Oxe2x80x94; thioethers of benzyl group, etc., thioesters of benzoyl group, etc., thiocarbonates of t-butyl carbonate, etc. when it is xe2x80x94Sxe2x80x94; benzyl group, formyl group, etc. when it is xe2x80x94NR21xe2x80x94 or xe2x80x94NR23xe2x80x94; and t-butyldimethylsilyloxy group, methylthio group, etc. when it is xe2x80x94(Cxe2x95x90O)NR21 or xe2x80x94(Cxe2x95x90O)NR23), and the compound [V] can be produced by introducing Z into the compound [IV] or the compound [IX] can be produced by introducing Z or R7 into the compound [VIII] to facilitate the development of synthesis. For example, when X3 or X4 in the compound [III] or [VII] is xe2x80x94Oxe2x80x94, the debenzylated intermediate [IV] or [VIII] can be produced from the compound [III] or [VII] by hydrogenation by the use of benzyl group as the group Z1. Further, the introduction of Z into the compound [IV] gives the compound [V] and the introduction of Z or R7 into the compound [VIII] gives the compound [IX]. In this case, R3 is preferably a C1-C4 hydrocarbon group among the groups defined in the formula (1) and the formula (2) from the viewpoint of the handling in synthesis. In other words, the compound of the formula (1) or formula (2) wherein R3 is hydrogen atom is produced preferably by introducing the group Z into the intermediate [IV] or introducing the group Z or the group R7 into the intermediate [VIII] and hydrolyzing the group CO2R3 (i.e. the group R3 is a C1-C4 hydrocarbon group).
There is no particular restriction on the method for introducing the group Z of the formula (3)-1 and the formula (3)-2 or the group R7 of the formula (5)-1 and the formula (5)-2 into the compound [IV] or [VIII], and the introduction can be carried out for example by using a reactant ZX5, R7X5, etc. An alcohol and an alkyl halide are concrete examples of ZX5 or R7X5 when X3 and X4 are xe2x80x94Oxe2x80x94. The objective compound [V] containing introduced group Z or the compound [IX] containing introduced group Z or R7 can be produced, in the case of using an alcohol as the ZX5 or R7X5, by using ZOH or R7OH, triphenyl phosphine (which may be replaced with tributyl phosphine, etc.), diethyl azodicarboxylate [which may be replaced with diisopropyl azodicarboxylate or 1,1-azobis(N,N-dimethylformamide)] and carrying out Mitsunobu synthesis or its analogous reaction in a proper solvent (e.g. N-methylmorpholine or tetrahydrofuran) at a proper temperature condition. In the case of using an alkyl halide, etc., i.e. using a halogen atom as the eliminable group X5, the objective compound [V] or [IX] can be produced by carrying out the reaction in the presence of a proper base such as sodium hydride, potassium carbonate or triethylamine in a proper solvent (e.g. dimethylformamide, tetrahydrofuran, acetonitrile or methylene chloride) under a proper temperature condition.
When the group X3 is xe2x80x94NR21 or the group X4 is xe2x80x94NR23, the group Z in the formula (3)-1 or the formula (3)-2 or the group R7 in the formula (5)-1 or the formula (5)-2 can be introduced by the above reaction similar to the case that the group X3 or X4 is xe2x80x94Oxe2x80x94. When the group X3 or X4 is xe2x80x94Sxe2x80x94, the compound ZX5 is an alkyl halide derivative, etc. In the case of synthesizing a compound containing xe2x80x94NHxe2x80x94, xe2x80x94NH2xe2x80x94, xe2x80x94CO2H, xe2x80x94OH, xe2x80x94SH, etc., in the group Z of the compound [V] or [IX] and further containing a substituent introduced into these functional groups, a compound of formula Z2X5 (there is no particular definition of Z2, however, it is a group produced by introducing a proper protecting group into xe2x80x94NH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94OH or xe2x80x94SH in the side chain) having proper protecting group introduced into xe2x80x94NH, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94OH or xe2x80x94SH is synthesized beforehand, the synthesized compound is made to react with the compound [IV] or [VIII] by the aforementioned method to introduce the group Z2, the protecting group of xe2x80x94NHxe2x80x94, xe2x80x94NH2, xe2x80x94CO2H, xe2x80x94OH or xe2x80x94SH in the group Z2 is removed, the product is used as an intermediate and various substituents are introduced into the intermediate to obtain the objective new compound having the group Z. When the group xe2x80x94CO2R3 is an ester, it can be induced as necessary into a carboxylic acid compound by hydrolyzing the ester xe2x80x94CO2R3.
Concrete example of the synthesizing process is the protection of the amino group of trans-4-aminocyclohexanol with benzyl group beforehand to obtain a dibenzyl compound, Mitsunobu reaction of the product with an intermediate [IV] or [VIII], debenzylation of the product to obtain an amino compound and the reaction with a reagent having a group to be introduced, for example, an acid chloride, sulfonyl chloride, etc., to obtain an amide compound, a sulfonamide compound, etc., as the objective compound. When the group xe2x80x94CO2R3 is an ester, a carboxylic acid compound can be produced as necessary by hydrolyzing the group xe2x80x94CO2R3. Also in this case, the group R3 is preferably a C1-C4 lower hydrocarbon group among the above definition in the formula (1) and the formula (2) from the viewpoint of handleability in synthesis, namely, a compound wherein R3 is hydrogen atom is preferably produced by the hydrolysis of xe2x80x94CO2R3.
A compound of the formula (1) or (2) wherein X1, X3 and X4 are each xe2x80x94(Sxe2x95x90O)xe2x80x94 or xe2x80x94(Oxe2x95x90Sxe2x95x90O)xe2x80x94 or A is Nxe2x86x92O can be produced by oxidizing a corresponding compound wherein X1, X3 or X4 are S or A is N. Although there is no particular restriction on the stage for oxidizing S or N in the above case, the objective oxidized product can be produced e.g. by oxidizing the non-oxidized compound [V] or [IX] with a general oxidizing agent such as peroxide or NBS.
A compound of the formula (1) or (2) wherein X3 or X4 is xe2x80x94(Cxe2x95x90O)xe2x80x94 can be synthesized e.g. by introducing ZCO or R7CO by Friedel-Crafts reaction at an arbitrary reaction stage. As an alternative, in the case of using a compound having carboxylic acid group at a position corresponding to the X3 or X4 on the benzene ring or naphthalene ring of the formula (3)-1, (3)-2, (5)-1 or (5)-2, the carboxylic acid can be converted into a ketone by activating the carboxylic acid with carbodiimidazole, etc., converting into an amide with N-methoxy-N-methylamine and reacting with a Grignard reagent of group Z or group R7 or lithium anion. When a raw material having carboxylic acid group at a position corresponding to the group X3 or X4 of the formula (3)-1, (3)-2, (5)-1 or (5)-2 is unavailable, a compound having methyl group, aldehyde group or xe2x80x94CH2OH at the corresponding position can be converted into carboxylic acid by oxidization. A compound having cyano group at the corresponding group can be converted into carboxylic acid by the hydrolysis of the cyano group. Further, even a compound having only hydrogen atom at the corresponding position can be converted into a carboxylic acid e.g. by the carboxylation with carbon dioxide.
When the group X3 is xe2x80x94NR21(Cxe2x95x90O) or the group X4 is xe2x80x94NR23(Cxe2x95x90O) (in this case, the N of xe2x80x94NR21(Cxe2x95x90O) is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2 and the N of xe2x80x94NR23(Cxe2x95x90O) is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2. The definition of R21 is same as the one shown in the formula (3)-1 and the formula (3)-2 and that of R23 is same as the one shown in the formula (5)-1 and the formula (5)-2.), the objective compound [V] or [IX] can be synthesized by reacting, at an arbitrary reaction stage, the compound [IV] or [VIII] with an acid chloride of the compound of the formula ZCO2H or its activated product in the case that the group xe2x80x94X3H of the compound [IV] or [VIII] is xe2x80x94NHR21 or reacting the compound [VIII] with an acid chloride of the formula R7CO2H or ZCO2H or its activated product in the case that the group xe2x80x94X4H of the compound [VIII] is xe2x80x94NHR23.
When the group X3 is xe2x80x94(Cxe2x95x90O)NR21 or the group X4 is xe2x80x94(Cxe2x95x90O)NR23 (in this case, the carbonyl group of xe2x80x94(Cxe2x95x90O)NR21 is bonded to the benzene ring or naphthalene ring in the formula (3)-1 or the formula (3)-2 and the carbonyl group of xe2x80x94(Cxe2x95x90O)NR23 is bonded to the benzene ring or naphthalene ring in the formula (5)-1 or the formula (5)-2. The definition of R21 is same as the one expressed in the formula (3)-1 and the formula (3)-2 and that of R23 is same as the one expressed in the formula (5)-1 and the formula (5)-2.), the objective compound can be synthesized by coupling, at an arbitrary reaction stage, a corresponding amine with a compound produced by activating a carboxylic acid with carbodiimidazole or oxalyl chloride, etc., using a compound having carboxylic acid group at a position corresponding to the X3 or the X4 of the formula (3)-1, the formula (3)-2, the formula (5)-1 or the formula (5)-2.
When the group R4 is an alkyl group, the objective compound is synthesized, although there is no restriction on the synthesis method, preferably by N-alkylating an anthranilic acid derivative [II] with a general alkylation agent, e.g. an alkyl halide such as an alkyl iodide before the coupling of the derivative with a compound [I] or [VI] in the above scheme and then coupling the alkylation product with the compound [I] or [VI].
Although there is no particular restriction on the process for the synthesis of the compounds [I] and [VI] which are raw materials for the above scheme, these compounds can be synthesized with reference to the description of the International Application WO95/32943 and the International Application 97/19910 or by the following method.
In the case of n is zero, these compounds can be synthesized according to the following scheme. 
In the above scheme, the definitions of R5, R6, R8, R9, X1, X3, X4 and A are same as the definitions in the formula (1), the formula (2), the formula (3)-1, the formula (3)-2, the formula (5)-1 and the formula (5)-2. The definition of Z1 is same as the aforementioned definition. The group R26 is hydrogen atom or a C1-C4 hydrocarbon group. As shown in the above scheme, these compounds can be produced by coupling the compound [X], [XI], [XII] or [XIII] having X7 as a nucleophilic site with the compound [XIV] or [XVI] having a proper eliminable group such as halogen atom on X8 using a proper base reagent and a proper solvent, concretely, the compound [XV] can be synthesized by coupling the compound [X] or [XI] with the compound [XIV] and the compound [XVII] can be synthesized by coupling the compound [X], [XI], [XII] or [XIII] with the compound [XVI]. When the group R26 is a hydrocarbon group, the compound [XV] and [XVII] can be converted into the corresponding carboxylic acid [I] and [VI] by the hydrolysis of the ester. Concretely, it can be synthesized by the following method.
In the case of producing the compound [XV] by the reaction of the compound [X] or [XI] with the compound [XIV] and in the case that the group X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the objective compound [XV] can be synthesized by reacting the compound [X] or [XI] wherein X7 is xe2x80x94OH or xe2x80x94SH with the compound [XIV] wherein X8 is F in the presence of a proper base reagent such as potassium carbonate (other examples of the reagent are sodium carbonate, potassium bicarbonate, etc.) in a proper solvent such as N,N-dimethylacetamide (other examples of the solvent are N,N-dimethylformamide, tetrahydrofuran, methylene chloride, etc.) under a proper temperature condition comprising the reaction at room temperature or under heating. In the above case, the group R26 of the compound [XIV] is preferably a C1-C4 hydrocarbon group from the viewpoint of the handleability in synthesis. In other words, it is preferable to obtain the carboxylic acid [I] by the ester hydrolysis of the compound [XV]. In the case of producing the compound [XVII] by the reaction of the compound [X], [XI], [XII] or [XIII] and in the case that the group X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the compound [XVII] can be synthesized by reacting the compound [X], [XI], [XII] or [XIII] wherein the group X7 is xe2x80x94OH or xe2x80x94SH with the compound [XVI] wherein the group X8 is xe2x80x94Cl in the presence of a proper base reagent such as sodium hydride (other examples of the reagent are potassium carbonate, sodium carbonate and potassium bicarbonate) in a proper solvent such as N,N-dimethylformamide under a proper temperature condition comprising the reaction at 0xc2x0 C. or under heating. Also in the above case, the group R26 of the compound [XVI] is preferably a C1-C4 hydrocarbon group from the viewpoint of the handleability in synthesis. In other words, it is preferable to obtain the carboxylic acid [VI] by the ester hydrolysis of the compound [XVII].
In the case of n is 1, these compounds can be synthesized according to the following scheme. 
In the above scheme, the definitions of R5, R6, R8, R9, X1, X3, X4 and A are same as the definitions in the formula (1), the formula (2), the formula (3)-1, the formula (3)-2, the formula (5)-1 and the formula (5)-2, and the definition of Z1 is same as aforementioned definition. As shown in the above scheme, these compound can be produced by coupling the compound [X], [XI], [XII] or [XIII] having X7 as a nucleophilic site with the compound [XVIII] or [XXI] having a proper eliminable group such as halogen atom on the group X8 using a proper base reagent and a proper solvent to synthesize the compound [XIX] from the compound [X] or [XI] or synthesize the compound [XXII] from the compound [X], [XI], [XII] or [XIII] and the product is subjected to rearrangement reaction to synthesize the thioamide [XX] from the compound [XIX] or synthesize the compound [XXIII] from the compound [XXII]. Furthermore, the products [XX] and [XXIII] can be converted into the compounds [I] and [VI] by hydrolysis. Concretely, the synthesis can be performed as follows.
In the case of producing the compound [XIX] by the reaction of the compound [X] or [XI] with the compound [XVIII] and in the case that the group X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the objective compound [XIX] can be synthesized by reacting the compound [X] or [XI] wherein X7 is xe2x80x94OH or xe2x80x94SH with the compound [XVIII] wherein X8 is xe2x80x94F in the presence of a proper base reagent such as potassium carbonate (other examples of the reagent are sodium carbonate, potassium bicarbonate and sodium hydride) in a proper solvent such as N,N-dimethylacetamide under a proper temperature condition comprising the reaction at room temperature or under heating. The product can be converted into the compound [I] by heating in the presence of S and morpholine to effect the rearrangement reaction and hydrolyzing the resultant thioamide [XX].
In the case of producing the compound [XXII] by the reaction of the compound [X], [XI], [XII] or [XIII] and in the case that the group X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, the compound [XXII] can be synthesized by reacting the compound [X], [XI], [XII] or [XIII] wherein the group X7 is xe2x80x94OH or xe2x80x94SH with the compound [XXI] wherein the group X8 is xe2x80x94Cl in the presence of a proper base reagent such as sodium hydride (other examples of the reagent are potassium carbonate, sodium carbonate and potassium bicarbonate) in a proper solvent such as N,N-dimethylformamide under a proper temperature condition comprising the reaction at 0xc2x0 C. or under heating. The product can be converted into the compound [VI] by heating in the presence of S and morpholine to effect the rearrangement reaction and hydrolyzing the resultant thioamide [XXIII].
Although there is no particular restriction on the process for the synthesis of the compounds [I] and [VI] wherein n is 2 or 3 and X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, these compounds can be synthesized with reference to a coupling method described in the paper of Journal of Medicinal Chemistry vol.40, no.4, sections 395-407 (1997) or similar methods.
Similarly, the compounds [I] and [VI] wherein n is 0 or 3 and X1 is xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94CH2xe2x80x94 can be synthesized, although there is no restriction on the process, with reference to a coupling method described in the paper of Journal of Medicinal Chemistry vol.40, no.4, sections 395-407 (1997) or similar methods.
The anthranilic acid derivative of the present invention and its pharmacologically permissible salt can be administered by peroral means or parenteral means such as intravenous injection, subcutaneous injection, intramuscular injection, transcutaneous administration, rectal infusion, nasal administration, eye instillation or by inhalation.
The form of the oral administration drug is, for example, tablet, pill, granule, powder, liquid, suspension, syrup or capsule.
A tablet can be formed by conventional method using an excipient such as lactose, starch and crystalline cellulose, a binder such as carboxymethylcellulose, methylcellulose and polyvinylpyrrolidone, a disintegrant such as sodium alginate, sodium bicarbonate and sodium laurylsulfate; etc.
A pill, granule and powder are also formable by conventional method using the above excipients, etc.
A liquid agent, suspension and syrup can be formed by conventional method using a glycerol ester such as tricaprylin and triacetin; an alcohol such as ethanol; water; a vegetable oil such as corn oil, cottonseed oil, coconut oil, almond oil, peanut oil and olive oil; etc.
A capsule can be formed by filling a granule, powder or liquid agent into a capsule made of gelatin, etc.
The agent for intravenous, subcutaneous or intramuscular administration is, for example, an injection composed of an aseptic aqueous or non-aqueous solution agent. The aqueous solution agent is produced e.g. by using physiological salt solution. The non-aqueous solution agent is produced e.g. by using propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable organic ester such as ethyl oleate, etc. These drugs may be incorporated as necessary with isotropic agent, antiseptic agent, wetting agent, emulsifying agent, dispersing agent, stabilizing agent, etc., and asepticized by proper treatments such as filtration through a bacteria-retaining filter, compounding of a disinfectant, heating treatment, irradiation treatment, etc. As an alternative, it can be used by preparing an aseptic solid preparation and dissolving the agent in aseptic water or an aseptic solvent for injection immediately before use.
The agent for percutaneous administration is an ointment agent, a cream agent, etc. These agents can be produced, by conventional method using an oil and fat such as castor oil or olive oil or petrolatum, etc., for an ointment agent and a fatty oil, diethylene glycol, an emulsifier such as sorbitan monofatty acid ester, etc., for a cream agent.
A conventional suppository such as gelatin soft capsule is used for the rectal administration.
The preparation for transnasal administration is supplied in the form of a liquid or powdery composition. The base for the liquid agent is water, salt solution, phosphate buffer solution, acetate buffer solution, etc., and the agent may further contain a surfactant, an antioxidant, a stabilizer, a preservative and a thickening agent. The base for the powdery agent is preferably a water-absorbing material, for example, easily water-soluble polyacrylic acid salts such as sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate; cellulose lower alkyl ethers such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium; polyethylene glycol polyvinylpyrrolidone, amylose, pullullan etc.; celluloses such as a scarcely water-soluble crystalline cellulose, xcex1-cellulose and crosslinked carboxymethylcellulose sodium; starches such as hydroxypropyl starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin and pectin; proteins such as gelatin, casein and casein sodium; gums such as gum arabic, tragacanth gum and glucomannan; crosslinked vinyl polymers such as polyvinylpolypyrrolidone, crosslinked polyacrylic acid and its salt, crosslinked polyvinyl alcohol and polyhydroxyethyl methacrylate; etc., or their mixture. The powdery agent may be incorporated further with an antioxidant, a colorant, a preservative, an antiseptic agent, a decay modifying agent, etc. Such liquid agent and powdery agent can be administered e.g. by using a spraying tool.
The eye instillation agent is an aqueous or non-aqueous instillation. The aqueous instillation can be produced by using sterilized pure water, physiological salt solution or proper aqueous solvent as the solvent, and includes an aqueous eye drop produced by using only a sterilized pure water as the solvent; a viscous eye drop added with a thickening agent such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose and polyvinylpyrrolidone; an aqueous suspension eye drop added with a surfactant or a suspension agent such as a polymer thickener; a solubilized eye drop added with a solubilizing agent such as a nonionic surfactant; etc. The non-aqueous instillation uses a non-aqueous solvent for injection as the solvent and includes a non-aqueous eye drop produced by using vegetable oil, liquid paraffin, mineral oil, propylene glycol, etc.; a non-aqueous suspension eye drop produced by using a thixotropic colloid such as aluminum monostearate as a suspension agent; etc. These preparations may be incorporated as necessary with an isotonic agent, a preservative, a buffer agent, an emulsifier, a stabilizing agent, etc., or asepticized by proper treatments such as filtration through a bacteria-retaining filter, compounding of a disinfectant, heating treatment, irradiation treatment, etc. As an alternative, it can be used by preparing an aseptic solid preparation and dissolving or suspending the agent in a proper aseptic solution immediately before use.
The dosage form for the administration to the eye other than an ophthalmic instillation is an eye ointment formed by using petrolatum, etc.; an application liquid produced by using dilute iodine tincture, zinc sulfate solution, methyl chloride rosaniline liquid, etc.; a scattering agent to directly apply fine powder of active component; an insertion agent produced by compounding or impregnating an active component in a proper base or a material and used by inserting into the eyelid, etc.
A solution or suspension of an active component and a conventional excipient for medicine is used for the inhalation, for example, in the form of an aerosol spray for inhalation. As an alternative, an active component having dried powdery form is administered by an inhalator or other device to enable the direct contact of the active component with the lung.
The administration dose of the compound of the present invention depends upon the kind of disease, administration path, condition, age, sex, body weight, etc., of the patient, etc. It is about 0.1 to 1,000 mg/day/head, preferably 1 to 300 mg/day/head in oral administration and about 0.1 to 100 mg/day/head, preferably 0.1 to 30 mg/day/head in parenteral administration such as intravenous, subcutaneous, intramuscular, percutaneous, rectal or nasal administration, ophthalmic instillation and inhalation, and the drug is prepared preferably to satisfy the above condition.
In the case of using the compound of the present invention as a preventing agent, such preparations may be administered beforehand according to each symptom by the administration method known as a method for the administration of preventing agent.
As shown in the following Examples, the anthranilic acid derivative of the present invention is effective for suppressing the highly proliferative L929 cell at a low concentration. Since the derivative is also effective for suppressing the proliferation of various other human cancer cells at a low concentration, it is extremely useful as a carcinostatic agent. Furthermore, as shown in the following Examples, the derivative also suppresses the production of IgE antibody from human lymphocyte by an antigen non-specific stimulation (IL-4+IL-10 (interleukin 10)+antiCD40Ab (anti-CD40 antibody)). Accordingly, the anthranilic acid derivative of the present invention is useful also as a preventive and/or therapeutic agent for allergic diseases caused by the production of IgE antibody such as bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, anaphylactic shock, mite allergy, pollinosis, food allergy, urticaria, ulcerative colitis, eosinophilic gastroenteritis and drug-induced rash.